Hepatology International (2020) 14:456–459
https://doi.org/10.1007/s12072-020-10044-y
EDITORIAL
Antioxidant therapy on ischemic hepatitis: here we are
and where do we go?
Hitoshi Maruyama1 · Shuichiro Shiina1
Received: 23 February 2020 / Accepted: 7 April 2020 / Published online: 29 April 2020
© Asian Pacific Association for the Study of the Liver 2020
Keywords  Ischemic hepatitis · N-acetylcysteine · Acute liver failure · Acute kidney injury
Abbreviations
IH Ischemic hepatitis
AST Aspartate aminotransferase
ALT Alanine aminotransferase
ALF Acute liver failure
HE Hepatic encephalopathy
ROS Reactive oxygen species
NAC  N-Acetylcysteine
GSH Glutathione
OR Odds ratio
AKI Acute kidney injury
Ischemic hepatitis (IH) is a clinical manifestation caused
by the insufficiency of hepatic flow volume and/or oxygen
content to maintain hepatocytes. IH, hypoxic hepatitis and
shock liver are in the same entity characterized by hepatic
necrosis around the central veins, showing a transient,
rapid, and considerable increase in liver enzymes (aspar-
tate aminotransferase [AST] and alanine aminotransferase
[ALT]) and significantly influences the prognosis [1–3].
It accounts for acute liver failure (ALF), which is a sud-
den and severe hepatic injury defined by an international
normalized ratio ≥ 1.5, neurologic dysfunction with any
degree of hepatic encephalopathy (HE), no prior evidence
of liver disease, and disease course of ≤ 26 weeks [4]. A
recent multicenter study of 387 patients in the US reported
4 common etiologies of ALF: IH (42.7%), pancreatobiliary
causes (12.3%), drug-induced liver injury (11.3%), and
acute viral hepatitis (11.3%) [5]. When the data were ana-
lyzed in patients with an ALT level > 5000, acetaminophen-
related liver injury and IH were the main causes (55.6%
* Hitoshi Maruyama
maru‑cib@umin.ac.jp
1
Department of Gastroenterology, Juntendo University, 2‑1‑1,
Hongo, Bunkyo‑ku, Tokyo 113‑8421, Japan
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and 33.3%, respectively). Similarly, in patients with an AST
level > 5000, IH and acetaminophen-related liver injury were
also the main causes (60.3% and 25.9%, respectively).
A large-scale systematic review of 24 papers includ-
ing 1782 patients reported that IH was present in 2.5% of
intensive care unit admissions, and 57% of patients with
liver enzymes > 1000 IU/L had IH.[1]. The vast majority
of patients with IH had cardiac comorbidities leading to
congestive hepatopathy. Systemic hypotension may be a
major pathogenesis of IH, although the pooled proportion of
patients with documented hypotension was only 52.9% [1].
In hepatology, acute variceal bleeding is a common cause
of IH in patients with cirrhosis (Fig. 1), known as a medical
emergency associated with a 20% mortality at 6 weeks [6].
Despite recent improvements in the quality of medical care,
IH is a critical condition that requires prompt and proper
treatment because the pooled rate of survival at discharge
was 51% (range 23.1–85.7%) [1].
Reactive oxygen species (ROS) production is a princi-
pal pathophysiology in IH; ischemic cell damage leads to
intracellular oxidant stress, and proinflammatory cytokines,
such as TNF-α, IL-1, and interferon-γ in hepatocytes play
a role in producing ROS. Ischemia also activates Kupffer
cell, which is the main source of ROS during the reper-
fusion period [7]. In addition, mitochondria are the major
intracellular source of ROS by the production with cellular
respiration.
N-acetylcysteine (NAC) is N-acetyl derivative of the
natural amino acid l-cysteine with the following: (i) direct
antioxidant activity, (ii) indirect antioxidant activity due
to a precursor of glutathione (GSH, the main endogenous
nucleophilic peptide that reacts with and neutralizes elec-
trophilic and hence damaging molecules such as N-acetyl-
p-benzoquinone imine, the electrophilic metabolite of
acetaminophen), (iii) enhancing effect of hepatosplanchnic
flow and function and (iv) breaking activity of disulfides
[8, 9]. NAC has been widely used as a mucolytic agent
Hepatology International (2020) 14:456–459 457
Fig. 1  Concept diagram of ischemic hepatitis following variceal
bleed. Increase of hepatosplanchnic perfusion and cytoprotection
against free-radical (oxidant) cellular damage are considered mecha-
nisms to reduce hepatic ischemic injury by N-acetylcysteine (NAC).
and for the treatment of acetaminophen poisoning. The
immediate administration of NAC is highly recommended
in confirmed cases of acetaminophen toxicity; it is best
administered within 8 h of ingestion [10] and is effective
up to 48 h post-ingestion [11]. An oral NAC (loading dose:
140 mg/kg by mouth or as a 5% diluted solution through
a nasogastric tube, maintenance dose: 70 mg/kg every 4 h
for a total of 17 doses) is as effective as intravenous NAC
(loading dose: 150 mg/kg in 5% dextrose solution over
15 min, maintenance dose: 50 mg/kg given over 4 h, fol-
lowed by 100 mg/kg over 16 h) and comparatively much
less expensive [12]. However, the latter is more frequently
used because most patients with acetaminophen-induced
hepatotoxicity experience significant nausea and vomiting.
Besides, NAC has side effects, mainly nausea and vomit-
ing, while rash, urticaria, and bronchospasm rarely occur
[13]. Even in cases without such side effects, altered men-
tal status due to acetaminophen-induced conditions make
it impossible to administer NAC orally [14].
*Effect of early intervention (early administration of NAC, improve-
ment of management for variceal bleeding and post-bleeding status)
is expected as a potential future new option
NAC can be superior to placebo/supportive treatment,
dimercaprol, and cysteamine in patients with acetaminophen
overdose [15]. NAC may also reduce mortality in patients
with fulminant hepatic failure caused by acetaminophen
overdose (Peto odds ratio [OR] 0.26) [15]. In a randomized
clinical trial comparing NAC with placebo in adults with
non-acetaminophen ALF, NAC was associated with an
improvement in transplant-free survival in a subgroup of
patients with grade 1 and grade 2 HE [16]. The positive
effect of NAC on heat injury-mediated IH to reduce reperfu-
sion injury was also reported [17]. These data suggest that
NAC therapy should be considered early in the course of IH
to improve transplant-free outcomes.
However, disagreements persist, as a recent system-
atic review demonstrated no difference in the overall
survival at 3  weeks between NAC (70%) and placebo
(66%), although NAC significantly improved the trans-
plant-free survival compared with placebo: 40% NAC vs
27% placebo [18]. An etiology-based subgroup analysis
also detected similar overall survival rates between the
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458
groups, NAC (79%) vs placebo (65%) with OR 0.50,
despite improved transplant-free survival in patients with
non-paracetamol drug-induced liver injury, NAC (58%)
vs placebo (27%) with OR 0.27. Therefore, there is insuf-
ficient evidence to support the effect of NAC in this regard,
and further investigation is warranted.
Against this background, in a study conducted in India,
Maiwall et  al. reported interesting results regarding the
effect of NAC on IH in cirrhosis patients accompanied by
acute variceal bleeding [19]. The strength of this work was
a prospective open-label randomized controlled trial with
two groups (standard of care plus NAC or a placebo group)
including a relatively large sample size of 220 patients.
Furthermore, the subjects had various etiologies (cirrhosis
mainly caused by alcohol abuse, and the others by viral,
autoimmune, non-alcoholic steatohepatitis, or cryptogenic),
not limited to drug-induced liver disease. The primary end-
point was the development of IH at day 5, and the secondary
end-points were survival at 6 weeks and the effect of NAC
on other complications, HE, acute kidney injury (AKI), and
infections (spontaneous bacterial peritonitis, pneumonia,
urinary tract infection, and/or bacteremia) at day 5. The
study demonstrated two major points: lower deaths due to
liver failure and reduced incidence of AKI. That is, the inci-
dence of AKI was the only factor that showed a significant
difference (p = 0.007) in the 5-day conditions; however, the
study demonstrated no data explaining the kidney mecha-
nism, as the authors acknowledged.
As with IH, ROS introduced by hypoxia and/or ischemia
is a key factor in the pathogenesis of AKI, because the kid-
neys are highly sensitive to the impaired conditions [20]. In
fact, the development of AKI indicates a close relationship
with oxidative damage to tubular cells and renal tissue [21],
as supported by animal studies demonstrating increased
oxidative damage and decreased tissue antioxidant [22,
23]. Additionally, there is a linkage between uremia and
increased circulating carbonyl and indole compounds, lead-
ing to enhanced systemic oxidative stress [24].
The application of antioxidant compounds has been used
to treat AKI. Studies have shown the beneficial effects of
NAC, being protective in ischemic, nephrotoxic, and rhabdo-
myolysis-induced AKI in animal models [25], improvement
of kidney function, renal GSH, and systemic oxidative stress,
and reduction of renal inflammation [20]. A recent animal
study reported the possibility of molybdenum-based poly-
oxometalate nanoclusters with preferential renal uptake as
novel nano-antioxidants for kidney protection; polyoxomet-
alate nanoclusters efficiently alleviated clinical symptoms
in mice subjected to AKI, as verified by dynamic positron
emission tomography imaging with 68 Ga-ethylenediami-
netetraacetate, serum tests, kidney tissue staining, and bio-
marker detection in the kidneys [26]. Taken together, the use
of antioxidants seems to play a significant role against AKI
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Hepatology International (2020) 14:456–459
irrespective of the presence/absence of IH, and the benefits
of NAC for IH might be dependent on the effect for AKI.
The data reported by Maiwall et al. may enhance the high
expectations of NAC in the clinical application for IH [19].
However, unlike the favorable effect to the kidneys, their
study reported no significant effect of NAC to control HE
and infections, which are also considerable complications
of IH in cirrhosis. That is, the use of NAC may not be a sole
therapeutic strategy, but just one of the multidisciplinary
treatments of IH. As future directions, firstly, it should be
an initial step to predict the occurrence of IH by an intensive
surveillance for those who have high-risk factors. Secondly,
the effect of early interventions, including an early adminis-
tration of NAC, and the improved management for variceal
bleeding and post-bleeding status typified by shock and
infections need to be examined as the next potential options
for IH. Anyhow, the wide range of clinical presentations may
feature treatment-resistive aspects of IH, and the study by
Maiwall et al. provide a rationale to pursue better therapies
for IH in cirrhosis patients.
Funding None.
Compliance with ethical standards 
Conflict of interest  Hitoshi Maruyama and Shuichiro Shiina have de-
clared that there is no conflict of interest.
Ethical approval  This article does not contain any studies with human
participants or animals performed by any of authors.
Informed consent  Not necessary, see above.
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